Details of a Researcher - Yamaguchi, Shintaro

Papers - Yamaguchi, Shintaro

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Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice.

Yamaguchi S, Franczyk MP, Chondronikola M, Qi N, Gunawardana SC, Stromsdorfer KL, Porter LC, Wozniak DF, Sasaki Y, Rensing N, Wong M, Piston DW, Klein S, Yoshino J.

Proc Natl Acad Sci U S A. (Proceedings of the National Academy of Sciences of the United States of America) 116 ( 47 ) 23822 - 23828 2019.11

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 00278424

Nicotinamide adenine dinucleotide (NAD(+)) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD(+) metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD(+) biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD(+)-SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD(+) synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD(+) biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

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Intestinal Epithelial NAD+ Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice

Nagahisa, T., Yamaguchi, S., Kosugi, S., Homma, K., Miyashita, K., Irie, J., Yoshino, J. and Itoh, H.

Endocrinology 163 ( 4 ) 2022.02

Corresponding author, Accepted, ISSN 0013-7227

Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

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Diurnal variation in PDK4 expression is associated with plasma free fatty acid availability in people.

Shintaro Yamaguchi, Anna C Moseley, Paloma Almeda-Valdes Kelly L Stromsdorfer, Michael P Franczyk, Adewole L Okunade,Bruce W Patterson, Samuel Klein, Jun Yoshino

J Clin Endocrinol Metab. (Journal of Clinical Endocrinology and Metabolism) 103 ( 3 ) 1068 - 1076 2018.03

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 0021972X

CONTEXT: Many biological pathways involved in regulating substrate metabolism display rhythmic oscillation patterns. In rodents, clock genes regulate circadian rhythms of metabolic genes and substrate metabolism. However, the interrelationships among substrate metabolism, metabolic genes, and clock genes have not been fully explored in people. OBJECTIVE: We tested the hypothesis that the diurnal expression pattern of pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic enzyme involved in fuel switching between glucose and free fatty acids (FFAs), is associated with plasma FFA concentration and clock genes. DESIGN AND METHODS: We analyzed peripheral blood mononuclear cells (PBMCs), subcutaneous adipose tissue, and plasma samples obtained serially during 24 hours from metabolically healthy women (n = 10) and evaluated the interrelationships among PDK4, plasma FFA, and clock genes. We also determined the potential mechanisms responsible for PDK4 transcriptional regulation by using primary human PBMCs and adipocytes. RESULTS: We found that PDK4 diurnal expression patterns were similar in PBMCs and adipose tissue (ρ = 0.84, P < 0.001). The diurnal variation in PBMC PDK4 expression correlated more strongly with plasma FFA and insulin (ρ = 0.86 and 0.63, respectively, both P < 0.001) concentrations than clock genes. Data obtained from primary culture experiments demonstrated that FFAs directly induced PDK4 gene expression, at least in part through activation of peroxisome proliferator-activated receptor α. CONCLUSIONS: Our results suggest that plasma FFA availability is an important regulator of diurnal expression patterns of PDK4, and we identify a novel interaction between plasma FFA and cellular diurnal rhythms in regulating substrate metabolism.

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Adipose tissue NAD(+) biology in obesity and insulin resistance: From mechanism to therapy

Shintaro Yamaguchi, Jun Yoshino

BIOESSAYS 39 ( 5 ) 2017.05

Research paper (scientific journal), Joint Work, Lead author, ISSN 0265-9247

Nicotinamide adenine dinucleotide (NAD(+) ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD(+) biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD(+) biosynthesis, together with its key downstream mediator, namely the NAD(+) -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD(+) biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD(+) biology.

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NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

Stromsdorfer, Kelly L., Yamaguchi, Shintaro*(*Co-first author), Yoon, Myeong Jin, Moseley, Anna C., Franczyk, Michael P., Kelly, Shannon C., Qi, Nathan, Imai, Shin-ichiro, Yoshino, Jun

CELL REPORTS 16 ( 7 ) 1851 - 1860 2016.08

Research paper (scientific journal), Joint Work, Lead author, ISSN 2211-1247

Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD(+) intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.

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NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward.

Logan RW1, Parekh PK, Kaplan GN, Becker-Krail DD, Williams WP 3rd, Yamaguchi S, Yoshino J, Shelton MA, Zhu X, Zhang H, Waplinger S, Fitzgerald E, Oliver-Smith J, Sundarvelu P, Enwright JF 3rd, Huang YH, McClung CA.

Mol Psychiatry. (Molecular Psychiatry) 24 ( 11 ) 1668 - 1684 2018.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 13594184

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.

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Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men.

Junichiro Irie, Emi Inagaki, Masataka Fujita, Hideaki Nakaya, Masanori Mitsuishi, Shintaro Yamaguchi, Kazuya Yamashita, Shuhei Shigaki, Takashi Ono, Hideo Yukioka, Hideyuki Okano, Yo-ichi Nabeshima, Shin-ichiro Imai, Masato Yasui, Kazuo Tsubota, Hiroshi Itoh

Endocr J (Endocrine Journal) 67 ( 2 ) 153 - 160 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 09188959

Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD(+)) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD(+) prevent these disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men. A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 h after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention. The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature. Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.

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NAD+-dependent deacetylase SIRT3 in adipocytes is dispensable for maintaining normal adipose tissue mitochondrial function and whole-body metabolism.

Porter LC, Franczyk MP, Pietka T, Yamaguchi S, Lin JB, Sasaki Y, Verdin E, Apte RS, Yoshino J.

Am J Physiol Endocrinol Metab. (American Journal of Physiology - Endocrinology and Metabolism) 315 ( 4 ) E520 - E530 2018.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 01931849

Mitochondrial dysfunction in adipose tissue is involved in the pathophysiology of obesity-induced systemic metabolic complications, such as type 2 diabetes, insulin resistance, and dyslipidemia. However, the mechanisms responsible for obesity-induced adipose tissue mitochondrial dysfunction are not clear. The aim of present study was to test the hypothesis that nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase sirtuin-3 (SIRT3) in adipocytes plays a critical role in adipose tissue mitochondrial biology and obesity. We first measured adipose tissue SIRT3 expression in obese and lean mice. Next, adipocyte-specific mitochondrial Sirt3 knockout (AMiSKO) mice were generated and metabolically characterized. We evaluated glucose and lipid metabolism in adult mice fed either a regular-chow diet or high-fat diet (HFD) and in aged mice. We also determined the effects of Sirt3 deletion on adipose tissue metabolism and mitochondrial biology. Supporting our hypothesis, obese mice had decreased SIRT3 gene and protein expression in adipose tissue. However, despite successful knockout of SIRT3, AMiSKO mice had normal glucose and lipid metabolism and did not change metabolic responses to HFD-feeding and aging. In addition, loss of SIRT3 had no major impact on putative SIRT3 targets, key metabolic pathways, and mitochondrial function in white and brown adipose tissue. Collectively, these findings suggest that adipocyte SIRT3 is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism. Contrary to our hypothesis, loss of SIRT3 function in adipocytes is unlikely to contribute to the pathophysiology of obesity-induced metabolic complications.

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Generation of kidney tubular organoids from human pluripotent stem cells

Yamaguchi, Shintaro, Morizane, Ryuji, Homma, Koichiro, Monkawa, Toshiaki, Suzuki, Sayuri, Fujii, Shizuka, Koda, Muneaki, Hiratsuka, Ken, Yamashita, Maho, Yoshida, Tadashi, Wakino, Shu, Hayashi, Koichi, Sasaki, Junichi, Hori, Shingo, Itoh, Hiroshi

SCIENTIFIC REPORTS 6 38353 2016.12

Research paper (scientific journal), Joint Work, Lead author, ISSN 2045-2322

Recent advances in stem cell research have resulted in methods to generate kidney organoids from human pluripotent stem cells (hPSCs), which contain cells of multiple lineages including nephron epithelial cells. Methods to purify specific types of cells from differentiated hPSCs, however, have not been established well. For bioengineering, cell transplantation, and disease modeling, it would be useful to establish those methods to obtain pure populations of specific types of kidney cells. Here, we report a simple two-step differentiation protocol to generate kidney tubular organoids from hPSCs with direct purification of KSP (kidney specific protein)-positive cells using anti-KSP antibody. We first differentiated hPSCs into mesoderm cells using a glycogen synthase kinase-3β inhibitor for 3 days, then cultured cells in renal epithelial growth medium to induce KSP+ cells. We purified KSP+ cells using flow cytometry with anti-KSP antibody, which exhibited characteristics of all segments of kidney tubular cells and cultured KSP+ cells in 3D Matrigel, which formed tubular organoids in vitro. The formation of tubular organoids by KSP+ cells induced the acquisition of functional kidney tubules. KSP+ cells also allowed for the generation of chimeric kidney cultures in which human cells self-assembled into 3D tubular structures in combination with mouse embryonic kidney cells.

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The role of microRNA-145 in human embryonic stem cell differentiation into vascular cells

Yamaguchi, Shintaro, Yamahara, Kenichi, Homma, Koichiro, Suzuki, Sayuri, Fujii, Shizuka, Morizane, Ryuji, Monkawa, Toshiaki, Matsuzaki, Yumi, Kangawa, Kenji, Itoh, Hiroshi

ATHEROSCLEROSIS 219 ( 2 ) 468 - 474 2011.12

Research paper (scientific journal), Joint Work, Lead author, ISSN 0021-9150

BACKGROUND: Recent studies have reported that microRNA-145 (miR-145) is a critical mediator in the regulation of proliferation, differentiation, and phenotype expression of smooth muscle cells (SMCs). Previously, we established a system for differentiating human ESCs into vascular cells including endothelial cells (ECs) and vascular smooth muscle cells (SMCs). In the present study, we investigated the role of miR-145 in the differentiation process from human ESCs into ECs and SMCs. METHODS AND RESULTS: Undifferentiated human ESCs were induced to differentiate into vascular lineage according to our established method. Quantitative RT-PCR analysis revealed that human ESC-derived precursor of SMCs (ES-pre-SMCs), similar to human aortic SMCs, expressed a significant amount of miR-145 as well as smooth muscle-specific proteins, compared to undifferentiated human ESCs, adult ECs, or ESC-derived ECs (ES-ECs). However, morphological analysis revealed that human ES-pre-SMCs appeared round and flattened in shape, though human aortic SMCs exhibited the typical spindle-like morphology of SMCs. In addition, Krüppel-like factor 4 and 5 (KLF4 and 5), direct targets of miR-145 and suppressors of smooth muscle differentiation, were upregulated in ES-pre-SMCs compared to aortic SMCs, indicating ES-pre-SMCs were not fully differentiated SMCs. Overexpression of miR-145 in ES-pre-SMCs upregulated the expression of smooth muscle markers, repressed KLF4 and 5 expressions, and changed their morphology into a differentiated spindle-like shape. Furthermore, by introduction of miR-145, ES-pre-SMC proliferation was significantly inhibited and carbachol-stimulated contraction of ES-pre-SMCs was significantly increased. In contrast, downregulation of miR-145 in ES-pre-SMCs upregulated KLF4 and 5 expressions, suppressed the expression of smooth muscle markers, and left unchanged their proliferation and contractility. In ES-ECs, miR-145 overexpression did not induce the synthesis of smooth muscle-related proteins nor suppress the expression of endothelial nitric oxide synthase. CONCLUSION: We showed that miR-145 can regulate the fate and phenotype of human ES-pre-SMCs as they become fully differentiated SMCs. Overexpression of miR-145 on human ES-pre-SMCs is a promising method to obtain functional mature SMCs from human ESCs, which are required for reliable experimental research in the fields of atherosclerosis, hypertension and other vascular diseases.

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Maternal circadian rhythms during pregnancy dictate metabolic plasticity in offspring

Yao, N., Kinouchi, K., Katoh, M., Ashtiani, K. C., Abdelkarim, S., Morimoto, H., Torimitsu, T., Kozuma, T., Iwahara, A., Kosugi, S., Komuro, J., Kato, K., Tonomura, S., Nakamura, T., Itoh, A., Yamaguchi, S., Yoshino, J., Irie, J., Hashimoto, H., Yuasa, S., Satoh, A., Mikami, Y., Uchida, S., Ueki, T., Nomura, S., Baldi, P., Hayashi, K. and Itoh, H.

Cell Metab 2025.01

ISSN 1550-4131

Tissue-level oscillation is achieved by tissue-intrinsic clocks along with network-dependent signals originating from distal organs and organismal behavior. Yet, it remains unexplored whether maternal circadian rhythms during pregnancy influence fetal rhythms and impact long-term susceptibility to dietary challenges in offspring. Here, we demonstrate that circadian disruption during pregnancy decreased placental and neonatal weight yet retained transcriptional and structural maturation. Intriguingly, diet-induced obesity was exacerbated in parallel with arrhythmic feeding behavior, hypothalamic leptin resistance, and hepatic circadian reprogramming in offspring of chronodisrupted mothers. In utero circadian desynchrony altered the phase-relationship between the mother and fetus and impacted placental efficiency. Temporal feeding restriction in offspring failed to fully prevent obesity, whereas the circadian alignment of caloric restriction with the onset of the active phase virtually ameliorated the phenotype. Thus, maternal circadian rhythms during pregnancy confer adaptive properties to metabolic functions in offspring and provide insights into the developmental origins of health and disease.

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Open-label, Randomized, Controlled, Crossover Trial on the Effect of Dapagliflozin in Patients with Autosomal Dominant Polycystic Kidney Disease Receiving Tolvaptan

Uchiyama, Kiyotaka, Kamano, Daisuke, Nagasaka, Tomoki, Hama, Eriko Yoshida, Shirai, Ryoichi, Sumura, Rena, Kusahana, Ei, Yanai, Akane, Nakayama, Takashin and Kimura, Takahide

Kidney International Reports 2025

ISSN 2468-0249

Early Initiation of Icodextrin Reduces Peritoneal Dialysis-Associated Peritonitis Risk: A Retrospective Cohort Study

Mitsuno, R., Nakayama, T., Morimoto, K., Uchiyama, K., Washida, N., Kusahana, E., Yoshida Hama, E., Tonomura, S., Yoshimoto, N., Hishikawa, A., Hagiwara, A., Azegami, T., Yoshino, J., Monkawa, T., Yoshida, T., Yamaguchi, S. and Hayashi, K.

Blood Purif 1 - 10 2024.12

ISSN 0253-5068

INTRODUCTION: Peritonitis is a common and serious complication of peritoneal dialysis (PD) that leads to its discontinuation and death. Icodextrin (ICO) improves peritoneal ultrafiltration and its early use reduces mortality. However, its effectiveness in reducing PD-associated infections remains to be elucidated. METHODS: This retrospective observational study enrolled patients who underwent PD between September 2011 and March 2020. The patients were classified into two groups: those who received ICO at the initiation of PD therapy (early ICO) and those who received ICO later or not at all (late/no ICO) and were followed up from PD induction until PD cessation, death, or 3 years had passed. RESULTS: Of the 82 patients (age, 61 [53-72] years), 21 received early ICO. During follow-up (36 [14-36] months), the incidence of PD-associated peritonitis was 0.17 episodes per patient-year. Log-rank tests indicated that PD-associated peritonitis and tunnel infection (TI)-free survival rates were significantly better with the early use of ICO than with late/no ICO (p = 0.02 and p = 0.01, respectively). The early use of ICO remained significantly associated with decreased incidence of both peritonitis and TI (hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06-0.69 and HR, 0.10; 95% CI, 0.01-0.78, respectively) using Cox regression analysis adjusted for potential confounders. CONCLUSION: Beginning ICO administration at the initiation of PD shows promise for mitigating the risks of PD-associated peritonitis and TI.

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Efficacy of sucrose and povidone-iodine mixtures in peritoneal dialysis catheter exit-site care

Nakayama, T., Morimoto, K., Uchiyama, K., Washida, N., Kusahana, E., Hama, E. Y., Mitsuno, R., Tonomura, S., Yoshimoto, N., Hishikawa, A., Hagiwara, A., Azegami, T., Yoshino, J., Monkawa, T., Yoshida, T., Yamaguchi, S. and Hayashi, K.

BMC Nephrol (BMC Nephrology) 25 ( 1 ) 151 2024.12

ISSN 1471-2369

BACKGROUND: Exit-site infection (ESI) is a common recurring complication in patients undergoing peritoneal dialysis (PD). Sucrose and povidone-iodine (SPI) mixtures, antimicrobial ointments that promote wound healing, have been used for the treatment of ulcers and burns, but their efficacy in exit-site care is still unclear. METHODS: This single-center retrospective observational study included patients who underwent PD between May 2010 and June 2022 and presented with episodes of ESI. Patients were divided into SPI and non-SPI groups and followed up from initial ESI onset until PD cessation, death, transfer to another facility, or June 2023. RESULTS: Among the 82 patients (mean age 62, [54-72] years), 23 were treated with SPI. The median follow-up duration was 39 months (range, 14-64), with an overall ESI incidence of 0.70 episodes per patient-year. Additionally, 43.1% of second and 25.6% of third ESI were caused by the same pathogen as the first. The log-rank test demonstrated significantly better second and third ESI-free survival in the SPI group than that in the non-SPI group (p < 0.01 and p < 0.01, respectively). In a Cox regression analysis, adjusting for potential confounders, SPI use was a significant predictor of decreased second and third ESI episodes (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.10-0.52 and HR, 0.22; 95%CI, 0.07-0.73, respectively). CONCLUSIONS: Our results showed that the use of SPI may be a promising option for preventing the incidence of ESI in patients with PD. TRIAL REGISTRATION: This study was approved by the Keio University School of Medicine Ethics Committee (approval number 20231078) on August 28, 2023. Retrospectively registered.

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Clinical relevance of proteinuria selectivity index and fractional excretion of sodium in patients with nephrotic syndrome

Nakayama, T., Azegami, T., Yamaguchi, S., Hirano, K., Komatsu, M., Fujii, K., Futatsugi, K., Urai, H., Kawaguchi, T., Itoh, T., Yoshimoto, N., Hagiwara, A., Hishikawa, A., Matsuda, H., Ando, T., Yamaji, Y., Murakami, M., Hashiguchi, A., Kaneko, Y., Yokoo, T. and Hayashi, K.

Sci Rep 14 ( 1 ) 23755 2024.12

ISSN 2045-2322

Proteinuria selectivity index (PSI) is a potential tool for histological classification and prediction of treatment response in nephrotic syndrome, but evidence is insufficient. Clinical relevance of fractional excretion of sodium (FENa) in nephrotic syndrome remains largely unexplored. This multicenter retrospective study included patients with nephrotic syndrome who underwent kidney biopsy between January 2012 and June 2022. Optimal cutoffs for predicting complete remission based on PSI and FENa were determined using receiver operating characteristic curves. Patients were divided into two groups using these cutoffs and followed until complete remission. Of the 611 patients included, 177 had minimal change disease (MCD), 52 had focal segmental glomerulosclerosis (FSGS), and 149 had membranous nephropathy (MN). Median (interquartile range) PSI were 0.14 (0.09-0.19) for MCD, 0.33 (0.23-0.40) for FSGS, and 0.20 (0.14-0.30) for MN. FENa were 0.24 (0.09-0.68), 1.03 (0.50-2.14), and 0.78 (0.41-1.28). Patients with low PSI and FENa had a higher incidence of complete remission. Cox regression analyses demonstrated that both parameters were associated with achieving complete remission (HR 2.73 [95% CI 1.97-3.81] and HR 1.93 [95% CI 1.46-2.55], respectively). PSI and FENa may be useful for histological classification and predicting remission in nephrotic syndrome.

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False-positive Serum Antiglomerular Basement Membrane Antibody due to Bovine Serum Albumin-containing Surgical Adhesive: A Case Report

Yoshida, R., Azegami, T., Yamaguchi, S., Hagiwara, A., Hishikawa, A., Yoshimoto, N., Hashiguchi, A. and Hayashi, K.

Kidney Med 6 ( 10 ) 100880 2024.10

ISSN 2590-0595

Antiglomerular basement membrane (GBM) disease has a poor prognosis. The rapid detection of serum anti-GBM antibody using an enzyme immunoassay, which has a high sensitivity and specificity, leads to an early diagnosis and improved prognosis. We report a case of acute kidney injury with false-positive anti-GBM antibody. A man in his early fifties underwent aortic arch replacement using bovine serum albumin (BSA)-containing surgical adhesion. After intravenous administration of vancomycin for a fever, he developed acute kidney injury without an abnormal urinalysis, and his anti-GBM antibody titer (fluorescence enzyme immunoassay [FEIA]) was 70.4 IU/mL. A kidney biopsy showed acute tubular injury and minor glomerular abnormalities without immunoglobulin G deposits, suggesting no evidence of anti-GBM glomerulonephritis. Consistent with the false-positive anti-GBM antibody test results, anti-GBM antibody determined using a chemiluminescent enzyme immunoassay was negative. A serum sample showed crossbinding to the FEIA plate from which the GBM antigen was removed. This finding indicated a nonspecific reaction to BSA, which contains a coating solution for the FEIA plate. This reaction was likely caused by anti-BSA antibody produced using BSA-containing surgical adhesion. Our findings suggest emerging challenges in diagnosing anti-GBM disease. Nephrologists must remain vigilant regarding false-positive anti-GBM antibody test results, particularly in cases evaluated with immunoassays that contain BSA.

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Diurnal variation in the association between the scan frequency of isCGM and CGM metrics: post hoc analysis of the ISCHIA study

Meguro, S., Sakane, N., Hosoda, K., Hirota, Y., Itoh, A., Kato, K., Kodani, N., Kuroda, A., Matsuhisa, M., Miura, J., Shimada, A., Tone, A., Toyoda, M. and Murata, T.

Diabetol Int 15 ( 4 ) 828 - 836 2024.10

ISSN 21901678

BACKGROUND AND AIMS: To investigate the association between the frequency of intermittent-scanning continuous glucose monitoring (isCGM) and diurnal variation of time in range (TIR), time above range (TAR), and time below range (TBR), we performed a post hoc analysis of the ISCHIA study, a multicenter, prospective, open-label, randomized crossover study of patients with type 1 diabetes mellitus. METHOD: Data of 93 people who completed the ISCHIA study were used. We calculated scan frequency, TAR, TIR, and TBR of four approximately 6-h intervals: 6:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), and 0:00-5:59 (night). The correlation between scan frequency and diurnal variation of CGM metrics was analyzed using nonparametric Spearman correlation analysis. RESULTS: More frequent scanning was associated with higher TIR in the afternoon (rho = 0.343, P < 0.001), evening (rho = 0.243, P = 0.019), and night (rho = 0.218, P = 0.036); furthermore, it was associated with lower TAR in the afternoon (rho = -0.275, P = 0.008) and TBR in the evening (rho = -0.235, P = 0.024). Concern about the effect of blood glucose fluctuation on social communication affected the number of scans during the day. Concerns about loneliness and hypoglycemia when alone also influenced the number of nighttime scans. CONCLUSION: Scan frequency is influenced by psychological factors. Afternoon scans were associated with the highest increase in TIR and decrease in TAR. Evening scans were linked to a reduction in TBR.

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Adipocyte-specific inactivation of NAMPT, a key NAD(+) biosynthetic enzyme, causes a metabolically unhealthy lean phenotype in female mice during aging

Qi, N., Franczyk, M. P., Yamaguchi, S., Kojima, D., Hayashi, K., Satoh, A., Ogiso, N., Kanda, T., Sasaki, Y., Finck, B. N., DeBosch, B. J. and Yoshino, J.

Am J Physiol Endocrinol Metab (American Journal of Physiology - Endocrinology and Metabolism) 327 ( 1 ) E81 - E88 2024.07

ISSN 01931849

Nicotinamide adenine dinucleotide (NAD(+)) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD(+) metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD(+) biosynthesis, mediated by a rate-limiting NAD(+) biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (≤4-mo-old), middle aged (10-14-mo-old), and old (≥18-mo-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic-euglycemic clamp procedure (HECP) demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPAR-γ) in an age-dependent manner. In addition, administration of a PPAR-γ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD(+)-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue, and whole body metabolic function in female mice during aging.NEW & NOTEWORTHY Defective NAD(+) metabolism is associated with aging and age-associated metabolic diseases. In the present study, we provided in-depth metabolic assessments in female mice with adipocyte-specific inactivation of a key NAD(+) biosynthetic enzyme NAMPT and revealed an unexpected role of adipose tissue NAMPT-NAD(+)-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue and whole body metabolic health during the aging process.

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Predictors of the effectiveness of isCGM usage in adults with type 1 diabetes mellitus: post-hoc analysis of the ISCHIA study

Murata, T., Hirota, Y., Hosoda, K., Kato, K., Kouyama, K., Kouyama, R., Kuroda, A., Matoba, Y., Matsuhisa, M., Meguro, S., Miura, J., Nishimura, K., Sakane, N., Shimada, A., Suzuki, S., Tone, A. and Toyoda, M.

Diabetol Int 15 ( 3 ) 400 - 405 2024.07

ISSN 21901678

AIM: The Effect of Intermittent-Scanning Continuous Glucose Monitoring to Glycemic Control Including Hypoglycemia and Quality of Life of Patients with Type 1 Diabetes Mellitus (ISCHIA) study was a randomized, crossover trial that reported the decrease in time below range (TBR) by the use of intermittent-scanning continuous glucose monitoring (isCGM) combined with structured education in adults with type 1 diabetes (T1D) treated by multiple daily injections. The participants were instructed to perform frequent scanning of the isCGM sensor (10 times a day or more) and ingest sugar when impending hypoglycemia is suspected by tracking the sensor glucose levels and the trend arrow. We conducted post-hoc analysis to identify factors affecting difference in TBR (∆TBR), in time in range (∆TIR), and in time above range (∆TAR). PARTICIPANTS AND METHODS: Data from 93 participants who completed the ISCHIA study were used. Multiple regression analyses were performed to identify factors affecting CGM metrics. RESULTS: Pearson's correlation analysis showed the negative association between log-transformed scan frequency and with ∆TBR (r = - 0.255, P = 0.015), while there was no significant association of log-transformed scan frequency with ∆TIR (r = 0.172, P = 0.102) and ∆TAR (r = 0.032, P = 0.761), respectively. The log-transformed scan frequency was an independent predictor of ∆TBR (Beta = - 7.712, P = 0.022), but not of ∆TIR(Beta = 7.203, P = 0.091) and of ∆TAR (Beta = 0.514, P = 0.925). CONCLUSIONS: Our findings suggest that more frequent scanning of isCGM may be beneficial to reduce TBR in T1D adults.

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Renal sinus fat is associated with intrarenal hemodynamic abnormalities independent of visceral fat in patients with chronic kidney disease

Kaneko, K., Mitsuno, R., Kojima, D., Azegami, T., Kosugi, S., Nakamura, T., Hashiguchi, A., Yamada, Y., Jinzaki, M., Yamaguchi, S., Itoh, H., Yoshino, J. and Hayashi, K.

Obes Res Clin Pract 18 ( 2 ) 118 - 123 2024.03

ISSN 1871403X

OBJECTIVE: Obesity is a risk factor of chronic kidney disease (CKD), contributing to the rising incidence of cardiometabolic diseases. Renal sinus fat (RSF) is an ectopic fat depot located at the renal cavity that could impair renal function and hemodynamic through compression of renal structures. The major purpose of this study was to explore the relationship between RSF accumulation and renal dysfunction in CKD patients. METHODS: We evaluated the associations between computed tomography measured RSF volume and key clinical and histologic parameters involved in renal function and hemodynamics in 132 well-characterized CKD patients who underwent renal biopsy (median age: 62 years; 63.6% men). RESULTS: RSF volume normalized by renal volume (RSF%) positively correlated with obesity-related traits such body mass index and visceral fat volume (VFV) (all P < 0.001) whereas it negatively correlated with estimated glomerular filtration rate (eGFR) (ρ = -0.42, P < 0.001) and 24-h urinary creatinine clearance (CCr) (ρ = -0.34, P < 0.001). Notably, we found robust positive correlations between RSF% and renal resistive index (RRI) measured by the Doppler ultrasound (ρ = 0.40, P < 0.001), and the histological severity of global glomerular sclerosis (ρ = 0.48, P < 0.001) and interstitial fibrosis and tubular atrophy (IFTA) (ρ = 0.35, P < 0.001). In the multivariate linear regression models, after accounting for potential confounders including VFV, RSF% remained significantly associated with CCr (β = -0.26, P < 0.001), RRI (β = 0.17, P = 0.022), global glomerular sclerosis (β = 0.21, P = 0.002), and IFTA (β = 0.17, P = 0.012). CONCLUSION: RSF accumulation is associated with renal dysfunction and hemodynamic abnormalities independent of visceral adiposity. Our results suggest that RSF may have a potential unique role in the pathogenesis of CKD.

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Nicotinamide mononucleotide, a potential future treatment in ocular diseases

Lee, D., Tomita, Y., Shinojima, A., Ban, N., Yamaguchi, S., Nishioka, K., Negishi, K., Yoshino, J. and Kurihara, T.

Graefes Arch Clin Exp Ophthalmol 262 ( 3 ) 689 - 700 2024.03

ISSN 0721832X

PURPOSE: The burden of ocular diseases has been gradually increasing worldwide. Various factors are suggested for the development and progression of ocular diseases, such as ocular inflammation, oxidative stress, and complex metabolic dysregulation. Thus, managing ocular diseases requires the modulation of pathologic signaling pathways through many mechanisms. Nicotinamide mononucleotide (NMN) is a bioactive molecule naturally found in life forms. NMN is a direct precursor of the important molecule nicotinamide adenine dinucleotide (NAD(+)), an essential co-enzyme required for enormous cellular functions in most life forms. While the recent experimental evidence of NMN treatment in various metabolic diseases has been well-reviewed, NMN treatment in ocular diseases has not been comprehensively summarized yet. In this regard, we aimed to focus on the therapeutic roles of NMN treatment in various ocular diseases with recent advances. METHODS: How we came to our current opinion with a recent summary was described based on our own recent reports as well as a search of the related literature. RESULTS: We found that NMN treatment might be available for the prevention of and protection from various experimental ocular diseases, as NMN treatment modulated ocular inflammation, oxidative stress, and complex metabolic dysregulation in murine models for eye diseases such as ischemic retinopathy, corneal defect, glaucoma, and age-related macular degeneration. CONCLUSION: Our current review suggests and discusses new modes of actions of NMN for the prevention of and protection from various ocular diseases and can urge future research to obtain more solid evidence on a potential future NMN treatment in ocular diseases at the preclinical stages.

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Association Between Renal Sinus Fat and Cardiometabolic and Renin-Angiotensin System Parameters in Primary Aldosteronism

Mitsuno, R., Kaneko, K., Nakamura, T., Kojima, D., Mizutani, Y., Azegami, T., Yamaguchi, S., Yamada, Y., Jinzaki, M., Kinouchi, K., Yoshino, J. and Hayashi, K.

J Endocr Soc (Journal of the Endocrine Society) 8 ( 1 ) bvad154 2024.01

ISSN 2472-1972

CONTEXT: Renal sinus fat (RSF) accumulation is associated with cardiometabolic diseases, such as obesity, diabetes, hypertension, and chronic kidney disease. However, clinical implications of RSF in primary aldosteronism (PA) remain unclear. OBJECTIVE: We aimed to investigate relationships between RSF volume and key cardiometabolic and renin-angiotensin system (RAS) parameters in PA patients and clarify the differences in these relationships between unilateral and bilateral subtypes. METHODS: We analyzed data obtained from well-characterized PA patients that involved 45 unilateral (median age: 52 years; 42.2% men) and 92 bilateral patients (51 years; 42.4% men). RESULTS: RSF volume normalized by renal volume (RSF%) was greater in the unilateral group than in the bilateral group (P < .05). RSF% was greater in men than in women (P < .05). RSF% positively correlated with parameters related to cardiometabolic risk, including age, body mass index, visceral fat volume, creatinine, triglycerides/high-density lipoprotein cholesterol ratio, uric acid, fasting glucose, and C-reactive protein regardless of PA subtypes (all P < .05). Intriguingly, RSF% positively correlated with plasma aldosterone concentration (PAC), aldosterone-to-renin ratio, and intact parathyroid hormone (iPTH) (all P < .05) in bilateral patients but did not correlate with RAS parameters and even showed an opposite trend in unilateral patients. In subgroup analyses by sex, these distinctions became more evident in women. After adjustment for potential confounders, RSF% remained positively correlated with PAC and iPTH in bilateral patients. CONCLUSION: Our results indicate that RSF accumulation is involved in cardiometabolic dysfunction associated with PA. However, there were distinct correlations between RSF volume and RAS parameters according to sex and PA subtypes.

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Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men

Yamaguchi, S., Irie, J., Mitsuishi, M., Uchino, Y., Nakaya, H., Takemura, R., Inagaki, E., Kosugi, S., Okano, H., Yasui, M., Tsubota, K., Hayashi, K., Yoshino, J. and Itoh, H.

Endocr J 71 ( 2 ) 153 - 169 2024

ISSN 09188959

Obesity and aging are major risk factors for several life-threatening diseases. Accumulating evidence from both rodents and humans suggests that the levels of nicotinamide adenine dinucleotide (NAD(+)), a regulator of many biological processes, declines in multiple organs and tissues with aging and obesity. Administration of an NAD(+) intermediate, nicotinamide mononucleotide (NMN), replenishes intracellular NAD(+) levels and mitigates aging- and obesity-associated derangements in animal models. In this human clinical study, we aimed to investigate the safety and effects of 8-week oral administration of NMN on biochemical, metabolic, ophthalmologic, and sleep quality parameters as well as on chronological alterations in NAD(+) content in peripheral tissues. An 8-week, single-center, single-arm, open-label clinical trial was conducted. Eleven healthy, middle-aged Japanese men received two 125-mg NMN capsules once daily before breakfast. The 8-week NMN supplementation regimen was well-tolerated; NAD(+) levels in peripheral blood mononuclear cells increased over the course of NMN administration. In participants with insulin oversecretion after oral glucose loading, NMN modestly attenuated postprandial hyperinsulinemia, a risk factor for coronary artery disease (n = 3). In conclusion, NMN overall safely and effectively boosted NAD(+) biosynthesis in healthy, middle-aged Japanese men, showing its potential for alleviating postprandial hyperinsulinemia.

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Combining hemodialysis with peritoneal dialysis improves cognitive function: a three-case report

Maruki, T., Nakayama, T., Morimoto, K., Uchiyama, K., Washida, N., Mitsuno, R., Tonomura, S., Hama, E. Y., Kusahana, E., Yoshimoto, N., Hishikawa, A., Hagiwara, A., Azegami, T., Yoshino, J., Monkawa, T., Yoshida, T., Yamaguchi, S. and Hayashi, K.

CEN Case Rep (CEN Case Reports) 13 ( 6 ) 517 - 521 2024

ISSN 2192-4449

Chronic kidney disease (CKD) is associated with multiple complications, with recent scholarly attention underscoring cognitive impairment as a salient manifestation. Considering societal aging, preserving cognitive function has emerged as an urgent medical concern. Prolonged dialysis, encompassing hemodialysis (HD) and peritoneal dialysis (PD), has been associated with a decline in cognitive function. Here, we present the cases of three patients undergoing PD who exhibited a noticeable improvement in cognitive function upon the initiation of HD. One patient had exhibited mild cognitive decline, whereas the remaining two presented more severe impairment. Apart from a mild tendency for fluid retention, none of the three patients exhibited abnormalities in physical or imaging examinations. Evaluation using the Japanese version of the Montreal Cognitive Assessment (MoCA-J) yielded decreased scores across multiple domains, notably in executive and attention functions. However, after HD initiation, all patients demonstrated a marked enhancement in multiple MoCA-J parameters, accompanied by a significant improvement in subjective symptoms. Moreover, improvements in anemia and hypoalbuminemia were observed in all three patients, whereas consistent trends in other parameters were absent. These clinical observations suggest that the integration of HD into the therapeutic regimen of patients undergoing PD may enhance cognitive function, highlighting the contributory roles of hemoglobin and albumin in CKD-associated cognitive impairment.

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Hemodialysis treatment of vancomycin-induced drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome in a patient undergoing peritoneal dialysis

Mitsuno, R., Nakayama, T., Uchiyama, K., Yoshimoto, N., Kusahana, E., Morimoto, K., Yoshino, J., Yoshida, T., Kanda, T., Yamaguchi, S. and Hayashi, K.

CEN Case Rep 13 ( 5 ) 339 - 345 2024

ISSN 2192-4449

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS), is a severe drug-induced hypersensitivity reaction with 10% mortality. To date, there is insufficient evidence regarding the association between DRESS/DIHS and serum levels of vancomycin (VCM). Here, we report the case of a 46-year-old woman undergoing peritoneal dialysis who developed VCM-induced DRESS/DIHS. She was hospitalized for peritonitis with abdominal pain and treated with VCM. On day 10 of hospitalization, her abdominal symptoms improved; however, fever, skin rash, lymphadenopathy, eosinophilia, atypical lymphocytes, and liver and renal dysfunction developed. Based on the clinical course and laboratory findings, we diagnosed the patient with DRESS/DIHS due to VCM. Since her serum VCM concentration was high at 39.8 μg/mL, hemodialysis (HD) was performed to remove VCM, which caused her symptoms to improve. However, serum levels of VCM rebounded and the same symptoms recurred. Therefore, we re-performed HD; no further relapse occurred. This clinical course showed that increased serum VCM levels were associated with DRESS/DIHS onset and severity, suggesting that it is a blood level-dependent disease and that removal of VCM by HD is a potential therapeutic option.

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Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report

Nagasaka, T., Uchiyama, K., Hama, E. Y., Kojima, D., Kaneko, K., Yoshimoto, N., Yasuda, I., Yamada, M., Miya, F., Suzuki, H., Tajima, T., Yamaguchi, S., Hayashi, K., Kanda, T., Hashiguchi, A., Kosaki, K. and Itoh, H.

CEN Case Rep 2024

ISSN 2192-4449

Transient receptor potential canonical 6 (TRPC6) variants, which were initially detected in adult-onset familial focal segmental glomerulosclerosis (FSGS), were also identified in pediatric-onset one. Here, we present a patient with adult-onset steroid-resistant nephrotic syndrome (SRNS) who harbored a likely pathogenic TRPC6 variant and partially responded to calcineurin inhibitors (CNIs). A 44-year-old woman with stable rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome was presented with nephrotic syndrome. Her renal biopsy results showed minor glomerular abnormalities. Upon admission, she was treated with steroids for around 4 weeks, but it was ineffective. After 1-2 weeks of cyclosporine A (CyA) administration, urine output increased, renal function improved without a decrease in proteinuria, and she was discharged. Her renal function was maintained for 2 months, but after a CyA dose reduction, she was again admitted to the hospital due to relapsing edema, decreased urine output, and worsening renal function. CyA was replaced by tacrolimus (TAC). A second renal biopsy showed nearly the same findings as the first except for tubulointerstitial lesions. After 1-2 weeks of TAC administration, urine output increased, and renal function improved. However, urinary protein levels did not decrease as before. After discharge, a whole exome analysis revealed a heterozygous splice donor site variant NM_004621.6;c.2644 + 1G > A in TRPC6. Genetic testing identified a novel splice donor site variant of TRPC6 in a patient with adult-onset SRNS, which prevented unnecessary steroid continuation. The safety and efficacy of CNI in TRPC6 glomerulopathy must be evaluated in future larger studies with longer follow-up.

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The proteinuria selectivity index value predicts the remission of IgA nephropathy: a retrospective cohort study

Mitsuno, R., Nakayama, T., Ito, W., Maruki, T., Nakamichi, R., Adachi, K., Yoshimoto, N., Hishikawa, A., Hagiwara, A., Yamaguchi, S., Monkawa, T., Yoshino, J., Hashiguchi, A., Azegami, T. and Hayashi, K.

Ren Fail 46 ( 2 ) 2423839 2024

ISSN 0886022X

IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and leads to end-stage kidney disease. The proteinuria selectivity index (PSI) has been used to assess the prognosis in nephrotic syndrome, but its predictive value in patients with IgAN remains unclear. This single-center retrospective cohort study included patients who diagnosed with IgAN between March 2012 and March 2020. The PSI was calculated at the time of kidney biopsy. Patients were followed up from the time of kidney biopsy to kidney replacement therapy, death, transfer to another facility, or study completion. Ninety-four patients with a median age of 51 years were enrolled and divided according to the cutoff value of PSI determined by the receiver operating characteristic curve analysis into low-PSI (PSI <0.243, n = 39) and high-PSI groups (PSI ≥0.243, n = 55). The median follow-up duration was 70 months. Rates of remission of proteinuria and survival without a two-fold increase in serum creatinine were significantly better in the low-PSI group (both p < 0.01, log-rank test). Cox regression analysis showed that a low PSI was significantly associated with an increased likelihood of remission of proteinuria and hematuria (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.02-3.85 and HR 1.75; 95% CI 1.01-3.13, respectively), and a decreased risk of a two-fold increase in serum creatinine (HR 0.10; 95% CI 0.01-0.81). In conclusion, The PSI could have the potential to support the assessment of the prognosis of IgAN, in addition to established prognostic markers, by reflecting the overall glomerular permeability.

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Successful renal transplantation following hemodialysis as bridging therapy in a patient with Fechtner syndrome: a case report and literature review

Hama, Eriko Yoshida, Yamaguchi, Shintaro, Uchiyama, Kiyotaka, Kojima, Daiki, Nagasaka, Tomoki, Yoshimoto, Norifumi, Tajima, Takaya, Kanda, Takeshi, Morimoto, Kohkichi and Yoshida, Tadashi

Renal Replacement Therapy 9 ( 1 ) 50 2023.12

ISSN 2059-1381

Background: Fechtner syndrome, also referred to as nonmuscle myosin heavy chain 9-related disease (MYH9-RD), is an autosomal-dominant genetic disorder. It is caused by abnormalities in the MYH9 gene, which encodes the nonmuscle conventional (class II) myosin heavy chain A (NMMHC-IIA). Its clinical manifestations include mild macrothrombocytopenia with leukocyte inclusions, hearing loss, cataracts, and renal failure. Case presentation: We present the case of a 34-year-old female patient with Fechtner syndrome in whom end-stage renal disease (ESRD) developed. During childhood, she presented with the typical symptoms of MYH9-RD, including thrombocytopenia, leukocyte inclusion bodies, onset of nephropathy, sensorineural hearing loss, and cataracts, wherein a clinical diagnosis of Fechtner syndrome was established. Her renal function deteriorated during adolescence. Furthermore, the patient underwent renal biopsy at the age of 18 years, which revealed focal segmental glomerulosclerosis. She was started on hemodialysis at the age of 33 years, followed by a living-donor renal transplantation after 5 months. She achieved a target platelet count of 50 × 109/L for arteriovenous fistula creation and 100 × 109/L for renal transplantation via platelet transfusions. Heparin use was avoided as an anticoagulant during hemodialysis. Since the patient expressed a desire for childbearing, genetic testing was performed, revealing an in-frame deletion of 21 nucleotides at 3195–3215 in exon 25 (A1065_A1072 del) of NMMHC-IIA, which has been reported to correlate with mild renal dysfunction. Our patient’s condition progressed into ESRD. Although genetic testing techniques have made great strides in recent years, our case clearly presents the difficulty in assuming an association between genetic abnormalities and clinical manifestations. Conclusions: Our case may provide further understanding of the management of ESRD in patients with MYH9-RD-related thrombocytopenia based on the results of genetic testing.

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Comparison of the effects of angiotensin receptor-neprilysin inhibitors and thiazide diuretic/renin-angiotensin system inhibitor combination therapy in hypertensive patients: a retrospective cohort study

Mitsuno, R., Uchiyama, K., Nakayama, T., Takahashi, R., Yoshimoto, N., Yamaguchi, S., Washida, N., Kanda, T., Hayashi, K. and Itoh, H.

J Hum Hypertens (Journal of Human Hypertension) 37 ( 12 ) 1049 - 1055 2023.12

ISSN 09509240

Angiotensin receptor-neprilysin inhibitors (ARNIs) have been approved as antihypertensive agents in Japan, and thiazide diuretics (TZDs) are widely used concomitantly with renin-angiotensin system inhibitors (RASIs) for hypertension. This retrospective study included patients with hypertension who switched from RASI to ARNI therapy (ARNI group) and those who were prescribed TZDs with RASIs (TZD/RASI group). Drug-related changes in the estimated glomerular filtration rate (eGFR), blood pressure (BP), body weight (BW), serum electrolytes, uric acid (UA), and triglyceride levels were compared between the two groups. Overall, 70 participants (31 and 39 in the ARNI and TZD/RASI groups, respectively) were enrolled and observed for a median of 2 months. According to linear mixed models, compared with the TZD/RASI group, the ARNI group exhibited a significant change in mean eGFR of 3.71 mL/min/1.73 m(2) [95% confidence interval (CI), 0.57-6.84; P = 0.02] from the time of switching drug to the next outpatient visit. Further, compared with the TZD/RASI group, the ARNI group exhibited significant changes in mean serum UA (-1.27; 95% CI, -1.66 to -0.88), sodium (1.22; 95% CI, 0.12 to -2.32), chloride (2.14; 95% CI, 0.75-3.52), and triglyceride (-52.1; 95% CI, -100.9 to -3.29) levels. Conversely, serum potassium levels, BW, and systolic and diastolic BP did not differ significantly between the two groups (P = 0.69, 0.44, 0.49, and 0.66, respectively). Compared with the combination therapy of TZD and RASI, ARNI therapy causes less renal dysfunction, hyperuricemia, and hypertriglyceridemia with fewer electrolyte abnormalities and no significant difference in antihypertensive effects.

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Clinical significance of serum urea-to-creatinine ratio in patients undergoing peritoneal dialysis

Tonomura, S., Uchiyama, K., Nakayama, T., Mitsuno, R., Kojima, D., Hama, E. Y., Nagasaka, T., Nishimura, E. S., Kusahana, E., Takahashi, R., Yoshimoto, N., Yamaguchi, S., Morimoto, K., Yoshida, T., Hayashi, K., Kanda, T., Washida, N. and Itoh, H.

Ther Apher Dial 27 ( 6 ) 1103 - 1112 2023.12

ISSN 1744-9979

INTRODUCTION: We aimed to determine the correlation between the serum urea-to-creatinine ratio and residual kidney function (RKF) in patients undergoing peritoneal dialysis (PD), as well as its predictive value for PD-related outcomes. METHODS: This study included a cross-sectional study to assess the correlation between serum urea-to-creatinine ratio and RKF in 50 patients on PD and a retrospective cohort study to assess the association between serum urea-to-creatinine ratio and PD-related outcomes in 122 patients who initiated PD. RESULTS: Serum urea-to-creatinine ratios had significant positive correlations with renal Kt/V and creatinine clearance values (r = 0.60, p < 0.001 and r = 0.61, p < 0.001, respectively). Additionally, serum urea-to-creatinine ratio was significantly associated with a lower risk of transfer to hemodialysis or PD/hemodialysis hybrid therapy (hazard ratio: 0.84, 95% confidence interval: 0.75-0.95). CONCLUSION: The serum urea-to-creatinine ratio can be an indicator of RKF and a prognostic factor in patients undergoing PD.

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Adipocyte NMNAT1 expression is essential for nuclear NAD(+) biosynthesis but dispensable for regulating thermogenesis and whole-body energy metabolism

Yamaguchi, S., Kojima, D., Iqbal, T., Kosugi, S., Franczyk, M. P., Qi, N., Sasaki, Y., Yaku, K., Kaneko, K., Kinouchi, K., Itoh, H., Hayashi, K., Nakagawa, T. and Yoshino, J.

Biochem Biophys Res Commun (Biochemical and Biophysical Research Communications) 674 162 - 169 2023.09

ISSN 0006291X

Nicotinamide adenine dinucleotide (NAD(+)) functions as an essential cofactor regulating a variety of biological processes. The purpose of the present study was to determine the role of nuclear NAD(+) biosynthesis, mediated by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), in thermogenesis and whole-body energy metabolism. We first evaluated the relationship between NMNAT1 expression and thermogenic activity in brown adipose tissue (BAT), a key organ for non-shivering thermogenesis. We found that reduced BAT NMNAT1expression was associated with inactivation of thermogenic gene program induced by obesity and thermoneutrality. Next, we generated and characterized adiponectin-Cre-driven adipocyte-specific Nmnat1 knockout (ANMT1KO) mice. Loss of NMNAT1 markedly reduced nuclear NAD(+) concentration by approximately 70% in BAT. Nonetheless, adipocyte-specific Nmnat1 deletion had no impact on thermogenic (rectal temperature, BAT temperature and whole-body oxygen consumption) responses to β-adrenergic ligand norepinephrine administration and acute cold exposure, adrenergic-mediated lipolytic activity, and metabolic responses to obesogenic high-fat diet feeding. In addition, loss of NMNAT1 did not affect nuclear lysine acetylation or thermogenic gene program in BAT. These results demonstrate that adipocyte NMNAT1 expression is required for maintaining nuclear NAD(+) concentration, but not for regulating BAT thermogenesis or whole-body energy homeostasis.

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Interactions between Intestinal Homeostasis and NAD(+) Biology in Regulating Incretin Production and Postprandial Glucose Metabolism

Nagahisa, T., Kosugi, S. and Yamaguchi, S.

Nutrients 15 ( 6 ) 2023.03

ISSN 2072-6643

The intestine has garnered attention as a target organ for developing new therapies for impaired glucose tolerance. The intestine, which produces incretin hormones, is the central regulator of glucose metabolism. Glucagon-like peptide-1 (GLP-1) production, which determines postprandial glucose levels, is regulated by intestinal homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD(+)) biosynthesis in major metabolic organs such as the liver, adipose tissue, and skeletal muscle plays a crucial role in obesity- and aging-associated organ derangements. Furthermore, NAMPT-mediated NAD(+) biosynthesis in the intestines and its upstream and downstream mediators, adenosine monophosphate-activated protein kinase (AMPK) and NAD(+)-dependent deacetylase sirtuins (SIRTs), respectively, are critical for intestinal homeostasis, including gut microbiota composition and bile acid metabolism, and GLP-1 production. Thus, boosting the intestinal AMPK-NAMPT-NAD(+)-SIRT pathway to improve intestinal homeostasis, GLP-1 production, and postprandial glucose metabolism has gained significant attention as a novel strategy to improve impaired glucose tolerance. Herein, we aimed to review in detail the regulatory mechanisms and importance of intestinal NAMPT-mediated NAD(+) biosynthesis in regulating intestinal homeostasis and GLP-1 secretion in obesity and aging. Furthermore, dietary and molecular factors regulating intestinal NAMPT-mediated NAD(+) biosynthesis were critically explored to facilitate the development of new therapeutic strategies for postprandial glucose dysregulation.

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Case report: Importance of early and continuous tocilizumab therapy in nephrotic syndrome associated with idiopathic multicentric Castleman disease: A case series

Kojima D., Yamaguchi S., Hashiguchi A., Hayashi K., Uchiyama K., Yoshimoto N., Adachi K., Nakayama T., Nishioka K., Tajima T., Morimoto K., Yoshino J., Yoshida T., Monkawa T., Kanda T., Itoh H.

Frontiers in Medicine (Frontiers in Medicine) 9 2023.01

Idiopathic multicentric Castleman disease (iMCD) is a systemic and polyclonal lymphoproliferative disease involving multiple organs, including the kidneys, due to the overproduction of interleukin-6 (IL-6). Recently, several reports have suggested that excessive IL-6 actions in iMCD could have a causal relationship with the development of diverse histopathological renal manifestations that cause nephrotic syndrome. However, the treatment for such cases remains unclear. We report a series of three cases of nephrotic syndrome due to iMCD that helps to delineate the importance of early and continuous therapy with the anti-interleukin-6 receptor antibody tocilizumab. First, treatment was suspended for infectious control, and the patient presented with nephrotic syndrome due to diffuse mesangial and endocapillary hypercellularity without immune deposits complicating acute kidney injury. Second, iMCD was treated with prednisolone alone. The patient suddenly developed nephrotic syndrome due to immune-complex glomerulonephritis, not otherwise specified, complicated with acute kidney injury. In the third case, nephrotic syndrome secondary to membranous glomerulonephritis was diagnosed, with a skin rash and IgE antibodies to tocilizumab, and was therefore treated with prednisolone alone. In contrast to the first two cases, the third progressed to end-stage renal disease on hemodialysis. Taken together, this series suggests that clinicians should maintain clinical vigilance for iMCD as a possible underlying component of nephrotic syndrome, since iMCD presents with a variety of renal pathologies. Prompt initiation and continuous administration of tocilizumab are likely key determinants of renal outcomes in such cases. In particular, when tocilizumab is suspended due to infection or in the perioperative period, consideration of its expeditious resumption should be made, taking into account both the withdrawal period and systemic conditions.

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Antineutrophil cytoplasmic antibody-associated vasculitis predominantly manifesting tubulointerstitial nephritis: A case report

Nishioka, K., Yamaguchi, S., Hashiguchi, A., Yoshimoto, N., Tajima, T., Yasuda, I., Uchiyama, K., Kaneko, K., Aso, M., Yoshino, J., Monkawa, T., Kanda, T., Hayashi, K. and Itoh, H.

SAGE Open Med Case Rep (SAGE Open Medical Case Reports) 11 2050313X231197324 2023.01

ISSN 2050-313X

The common histopathology of antineutrophil cytoplasmic antibody-associated vasculitis comprises pauci-immune crescentic glomerulonephritis with concomitant tubulointerstitial nephritis. Tubulointerstitial nephritis in the absence of glomerular involvement in patients with antineutrophil cytoplasmic antibody-associated vasculitis is uncommon. We report a case of antineutrophil cytoplasmic antibody-associated vasculitis-associated acute kidney injury manifesting as tubulointerstitial nephritis without glomerulonephritis. A 75-year-old woman with fever, cough, and myalgia developed kidney dysfunction with inflammatory reactions and tubular-type proteinuria, without glomerular hematuria. A kidney biopsy revealed tubulointerstitial nephritis with arteritis. We ruled out important underlying etiologies of tubulointerstitial nephritis, including infection, drug reactions, and autoimmune diseases. Since chest high-resolution computed tomography demonstrated mild interstitial pneumonia in bilateral lower lung fields, myeloperoxidase antineutrophil cytoplasmic antibody was measured and found to be positive. Therefore, we diagnosed the patient with antineutrophil cytoplasmic antibody-associated vasculitis-associated tubulointerstitial nephritis but not glomerulonephritis, and interstitial pneumonia. The patient's kidney function and symptoms markedly improved with prednisolone treatment. Clinicians should maintain high-level vigilance for antineutrophil cytoplasmic antibody-associated vasculitis as a possible underlying component of tubulointerstitial nephritis, particularly when kidney function deteriorates with tubulointerstitial injuries without glomerular features.

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Prevention of hypoglycemia by intermittent-scanning continuous glucose monitoring device combined with structured education in patients with type 1 diabetes mellitus: A randomized, crossover trial

Diabetes Res Clin Pract 195 110147 2023.01

ISSN 0168-8227

AIMS: We conducted a randomized, crossover trial to compare intermittent-scanning continuous glucose monitoring (isCGM) device with structured education (Intervention) to self-monitoring of blood glucose (SMBG) (Control) in the reduction of time below range. METHODS: This crossover trial involved 104 adults with type 1 diabetes mellitus (T1DM) using multiple daily injections. Participants were randomly allocated to either sequence Intervention/Control or sequence Control/Intervention. During the Intervention period which lasted 84 days, participants used the first-generation FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA) and received structured education on how to prevent hypoglycemia based on the trend arrow and by frequent sensor scanning (≥10 times a day). Confirmatory SMBG was conducted before dosing insulin. The Control period lasted 84 days. The primary endpoint was the decrease in the time below range (TBR; <70 mg/dL). RESULTS: The time below range was significantly reduced in the Intervention arm compared to the Control arm (2.42 ± 1.68 h/day [10.1 %±7.0 %] vs 3.10 ± 2.28 h/day [12.9 %±9.5 %], P = 0.012). The ratio of high-risk participants with low blood glucose index >5 was significantly reduced (8.6 % vs 23.7 %, P < 0.001). CONCLUSIONS: The use of isCGM combined with structured education significantly reduced the time below range in patients with T1DM.

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Compared effectiveness of sodium zirconium cyclosilicate and calcium polystyrene sulfonate on hyperkalemia in patients with chronic kidney disease

Nakayama T., Yamaguchi S., Hayashi K., Uchiyama K., Tajima T., Azegami T., Morimoto K., Yoshida T., Yoshino J., Monkawa T., Kanda T., Itoh H.

Frontiers in Medicine (Frontiers in Medicine) 10 2023

Hyperkalemia is a well-recognized electrolyte abnormality in patients with chronic kidney disease (CKD). Potassium binders are often used to prevent and treat hyperkalemia. However, few studies have evaluated the difference in serum potassium (K+) level-lowering effect during the post-acute phase between the novel potassium binder, sodium zirconium cyclosilicate (ZSC), and conventional agents. This retrospective study included patients who received potassium binders (either ZSC or calcium polystyrene sulfonate [CPS]) in our hospital between May 2020 and July 2022. The patients were divided into the ZSC and CPS groups. After propensity score matching, we compared changes from baseline to the first follow-up point, at least 4 weeks after initiating potassium binders, in electrolytes including K+ level between the two groups. Of the 132 patients, ZSC and CPS were administered in 48 and 84 patients, respectively. After matching, 38 patients were allocated to each group. The ZSC group showed greater reduction in K+ levels than did the CPS group (P < 0.05). Moreover, a significant increase in serum sodium minus chloride levels, a surrogate marker for metabolic acidosis, was observed in the ZSC group (P < 0.05). Our results demonstrated that ZSC could potentially improve hyperkalemia and metabolic acidosis in patients with CKD.

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Hydrogen gas and preservation of intestinal stem cells in mesenteric ischemia and reperfusion

Yamamoto, R., Suzuki, S., Homma, K., Yamaguchi, S., Sujino, T. and Sasaki, J.

World J Gastrointest Surg 14 ( 12 ) 1329 - 1339 2022.12

ISSN 1948-9366

BACKGROUND: Patients with mesenteric ischemia frequently suffer from bowel necrosis even after revascularization. Hydrogen gas has showed promising effects for ischemia-reperfusion injury by reducing reactive oxygen species in various animal and clinical studies. We examined intestinal tissue injury by ischemia and reperfusion under continuous initiation of 3% hydrogen gas. AIM: To clarify the treatment effects and target cells of hydrogen gas for mesenteric ischemia. METHODS: Three rat groups underwent 60-min mesenteric artery occlusion (ischemia), 60-min reperfusion following 60-min occlusion (reperfusion), or ischemia-reperfusion with the same duration under continuous 3% hydrogen gas inhalation (hydrogen). The distal ileum was harvested. Immunofluorescence staining with caspase-3 and leucine-rich repeat-containing G-protein-coupled 5 (LGR5), a specific marker of intestinal stem cell, was conducted to evaluate the injury location and cell types protected by hydrogen. mRNA expressions of LGR5, olfactomedin 4 (OLFM4), hairy and enhancer of split 1, Jagged 2, and Neurogenic locus notch homolog protein 1 were measured by quantitative polymerase chain reaction. Tissue oxidative stress was analyzed with immunostaining for 8-hydroxy-2'-deoxyguanosine (8-OHdG). Systemic oxidative stress was evaluated by plasma 8-OHdG. RESULTS: Ischemia damaged the epithelial layer at the tip of the villi, whereas reperfusion induced extensive apoptosis of the cells at the crypt base, which were identified as intestinal stem cells with double immunofluorescence stain. Hydrogen mitigated such apoptosis at the crypt base, and the LGR5 expression of the tissues was higher in the hydrogen group than in the reperfusion group. OLFM4 was also relatively higher in the hydrogen group, whereas other measured RNAs were comparable between the groups. 8-OHdG concentration was high in the reperfusion group, which was reduced by hydrogen, particularly at the crypt base. Serum 8-OHdG concentrations were relatively higher in both reperfusion and hydrogen groups without significance. CONCLUSION: This study demonstrated that hydrogen gas inhalation preserves intestinal stem cells and mitigates oxidative stress caused by mesenteric ischemia and reperfusion.

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Nicotinamide Mononucleotide Protects against Retinal Dysfunction in a Murine Model of Carotid Artery Occlusion

Lee, D., Tomita, Y., Miwa, Y., Jeong, H., Shinojima, A., Ban, N., Yamaguchi, S., Nishioka, K., Negishi, K., Yoshino, J. and Kurihara, T.

Int J Mol Sci 23 ( 23 ) 2022.12

ISSN 16616596

Cardiovascular abnormality-mediated retinal ischemia causes severe visual impairment. Retinal ischemia is involved in enormous pathological processes including oxidative stress, reactive gliosis, and retinal functional deficits. Thus, maintaining retinal function by modulating those pathological processes may prevent or protect against vision loss. Over the decades, nicotinamide mononucleotide (NMN), a crucial nicotinamide adenine dinucleotide (NAD(+)) intermediate, has been nominated as a promising therapeutic target in retinal diseases. Nonetheless, a protective effect of NMN has not been examined in cardiovascular diseases-induced retinal ischemia. In our study, we aimed to investigate its promising effect of NMN in the ischemic retina of a murine model of carotid artery occlusion. After surgical unilateral common carotid artery occlusion (UCCAO) in adult male C57BL/6 mice, NMN (500 mg/kg/day) was intraperitoneally injected to mice every day until the end of experiments. Electroretinography and biomolecular assays were utilized to measure ocular functional and further molecular alterations in the retina. We found that UCCAO-induced retinal dysfunction was suppressed, pathological gliosis was reduced, retinal NAD(+) levels were preserved, and the expression of an antioxidant molecule (nuclear factor erythroid-2-related factor 2; Nrf2) was upregulated by consecutive administration of NMN. Our present outcomes first suggest a promising NMN therapy for the suppression of cardiovascular diseases-mediated retinal ischemic dysfunction.

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Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury

Lee, D., Tomita, Y., Miwa, Y., Shinojima, A., Ban, N., Yamaguchi, S., Nishioka, K., Negishi, K., Yoshino, J. and Kurihara, T.

Int J Mol Sci 23 ( 19 ) 2022.10

ISSN 16616596

Retinal ischemia/reperfusion (I/R) injury can cause severe vision impairment. Retinal I/R injury is associated with pathological increases in reactive oxygen species and inflammation, resulting in retinal neuronal cell death. To date, effective therapies have not been developed. Nicotinamide mononucleotide (NMN), a key nicotinamide adenine dinucleotide (NAD(+)) intermediate, has been shown to exert neuroprotection for retinal diseases. However, it remains unclear whether NMN can prevent retinal I/R injury. Thus, we aimed to determine whether NMN therapy is useful for retinal I/R injury-induced retinal degeneration. One day after NMN intraperitoneal (IP) injection, adult mice were subjected to retinal I/R injury. Then, the mice were injected with NMN once every day for three days. Electroretinography and immunohistochemistry were used to measure retinal functional alterations and retinal inflammation, respectively. The protective effect of NMN administration was further examined using a retinal cell line, 661W, under CoCl(2)-induced oxidative stress conditions. NMN IP injection significantly suppressed retinal functional damage, as well as inflammation. NMN treatment showed protective effects against oxidative stress-induced cell death. The antioxidant pathway (Nrf2 and Hmox-1) was activated by NMN treatment. In conclusion, NMN could be a promising preventive neuroprotective drug for ischemic retinopathy.

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Late Dialysis Modality Education Could Negatively Predict Peritoneal Dialysis Selection

Nakayama, T., Nishioka, K., Uchiyama, K., Morimoto, K., Kusahana, E., Washida, N., Yamaguchi, S., Azegami, T., Yoshida, T. and Itoh, H.

J Clin Med 11 ( 14 ) 2022.07

ISSN 2077-0383

Patients with end-stage renal disease are less likely to choose peritoneal dialysis (PD) as renal replacement therapy (RRT). The reasons for this biased selection are still poorly understood. In this study, we evaluated the effect of the timing of RRT education on PD selection. This single-center retrospective observational study included patients who initiated maintenance dialysis at our hospital between April 2014 and July 2021. A logistic regression analysis was performed to investigate the association of RRT education timing with PD selection. Among the 355 participants (median age [IQR] 70 (59−79) years; 28.7% female), 53 patients (14.9%) and 302 patients (85.1%) selected PD and hemodialysis, respectively. Multivariate analysis demonstrated that high estimated glomerular filtration (eGFR) at RRT education positively predicted PD selection (p < 0.05), whereas old age (p < 0.01) and high Charlson comorbidity index (p < 0.05) were negative predictors of PD selection. Female sex (p = 0.44), welfare public assistance (p = 0.78), living alone (p = 0.25), high geriatric nutritional risk index (p = 0.10) and high eGFR at first visit to the nephrology department (p = 0.83) were not significantly associated with PD selection. Late RRT education could increase the biased selection of dialysis modality.

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Development of Alveolar Hemorrhage After Pfizer-BioNTech COVID-19 mRNA Vaccination in a Patient With Renal-Limited Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Case Report

Nishioka K., Yamaguchi S., Yasuda I., Yoshimoto N., Kojima D., Kaneko K., Aso M., Nagasaka T., Yoshida E., Uchiyama K., Tajima T., Yoshino J., Yoshida T., Kanda T., Itoh H.

Frontiers in Medicine (Frontiers in Medicine) 9 2022.04

Since the coronavirus disease 2019 (COVID-19) pandemic continues and a new variant of the virus has emerged, the COVID-19 vaccination campaign has progressed. Rare but severe adverse outcomes of COVID-19 vaccination such as anaphylaxis and myocarditis have begun to be noticed. Of note, several cases of new-onset antineutrophil cytoplasmic antibody-associated vasculitis (AAV) after COVID-19 mRNA vaccination have been reported. However, relapse of AAV in remission has not been recognized enough as an adverse outcome of COVID-19 vaccination. We report, to our knowledge, a first case of renal-limited AAV in remission using every 6-month rituximab administration that relapsed with pulmonary hemorrhage, but not glomerulonephritis, following the first dose of the Pfizer-BioNTech COVID-19 vaccine. The patient received the COVID-19 vaccine more than 6 months after the last dose of rituximab according to the recommendations. However, his CD19+ B cell counts were found to be increased after admission, indicating that our case might have been prone to relapse after COVID-19 vaccination. Although our case cannot establish causality between AAV relapse and COVID-19 mRNA vaccination, a high level of clinical vigilance for relapse of AAV especially in patients undergoing rituximab maintenance therapy following COVID-19 vaccination should be maintained. Furthermore, elapsed time between rituximab administration and COVID-19 mRNA vaccination should be carefully adjusted based on AAV disease-activity.

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Circadian transcription factor NPAS2 and the NAD(+) -dependent deacetylase SIRT1 interact in the mouse nucleus accumbens and regulate reward

Becker-Krail, D. D., Parekh, P. K., Ketchesin, K. D., Yamaguchi, S., Yoshino, J., Hildebrand, M. A., Dunham, B., Ganapathiraju, M. K., Logan, R. W. and McClung, C. A.

Eur J Neurosci (European Journal of Neuroscience) 55 ( 3 ) 675 - 693 2022

Accepted, ISSN 0953816X

Substance use disorders are associated with disruptions to both circadian rhythms and cellular metabolic state. At the molecular level, the circadian molecular clock and cellular metabolic state may be interconnected through interactions with the nicotinamide adenine dinucleotide (NAD(+) )-dependent deacetylase, sirtuin 1 (SIRT1). In the nucleus accumbens (NAc), a region important for reward, both SIRT1 and the circadian transcription factor neuronal PAS domain protein 2 (NPAS2) are highly enriched, and both are regulated by the metabolic cofactor NAD(+) . Substances of abuse, like cocaine, greatly disrupt cellular metabolism and promote oxidative stress; however, their effects on NAD(+) in the brain remain unclear. Interestingly, cocaine also induces NAc expression of both NPAS2 and SIRT1, and both have independently been shown to regulate cocaine reward in mice. However, whether NPAS2 and SIRT1 interact in the NAc and/or whether together they regulate reward is unknown. Here, we demonstrate diurnal expression of Npas2, Sirt1 and NAD(+) in the NAc, which is altered by cocaine-induced upregulation. Additionally, co-immunoprecipitation reveals NPAS2 and SIRT1 interact in the NAc, and cross-analysis of NPAS2 and SIRT1 chromatin immunoprecipitation sequencing reveals several reward-relevant and metabolic-related pathways enriched among shared gene targets. Notably, NAc-specific Npas2 knock-down or a functional Npas2 mutation in mice attenuates SIRT1-mediated increases in cocaine preference. Together, our data reveal an interaction between NPAS2 and SIRT1 in the NAc, which may serve to integrate cocaine's effects on circadian and metabolic factors, leading to regulation of drug reward.

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Importance of Adipose Tissue NAD+ Biology in Regulating Metabolic Flexibility

Franczyk, M. P., Qi, N., Stromsdorfer, K. L., Li, C., Yamaguchi, S., Itoh, H., Yoshino, M., Sasaki, Y., Brookheart, R. T., Finck, B. N., DeBosch, B. J., Klein, S. and Yoshino, J.

Endocrinology 162 ( 3 ) 2021.01

ISSN 0013-7227

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.

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A case of cerebral infarction caused by painless acute aortic dissection in autosomal dominant polycystic kidney disease

Yamaguchi, S., Wakino, S., Tokuyama, H. and Itoh, H.

CEN Case Rep (CEN case reports) 9 ( 2 ) 177 - 181 2020.05

ISSN 2192-4449

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder, characterized by the progressive formation of renal cysts. Although ADPKD is strongly associated with cerebral and cardiovascular complications, cerebral ischemia caused by dissection of thoracic and carotid arteries has rarely been reported. We report the case of a 71-year-old Japanese woman who complained of hemiparesis. She required maintenance hemodialysis therapy with a background of ADPKD. Cerebral infarction was initially diagnosed by excluding intracranial hemorrhage and aneurysm rupture that are recognized as common complications of ADPKD and thereby anticoagulation therapy was initiated. However, the patient was suspected as having painless aortic dissection because a chest X-ray examination showed expanded upper mediastinum. Sequential vascular imagings revealed dissection of the aorta, originating from brachiocephalic trunk to the right common carotid artery with mediastinal hematoma. The patient died from progression of dissection. Herein, we described a case of the ADPKD patient that an acute aortic dissection without any pain induced the occlusion of supplying vessels to the brain, resulting in cerebral ischemic symptoms. A high level of clinical vigilance for an acute aortic dissection should be maintained in the ADPKD population with sudden onset of neurological symptoms even in the absence of pain. Furthermore, the initiation of anticoagulation treatment for cerebral ischemia which may aggravate the risk of further dissection requires careful consideration.

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Potential significance of Nad+ biology translational research in super-aged Japan

Yamaguchi, Shintaro, Ito, Yutaka and Yoshino, Jun

Japanese Journal of Geriatrics 57 ( 3 ) 213 - 223 2020

ISSN 0300-9173

Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors

Hiratsuka, K., Monkawa, T., Akiyama, T., Nakatake, Y., Oda, M., Goparaju, S. K., Kimura, H., Chikazawa-Nohtomi, N., Sato, S., Ishiguro, K., Yamaguchi, S., Suzuki, S., Morizane, R., Ko, S. B. H., Itoh, H. and Ko, M. S. H.

Sci Rep (Scientific Reports) 9 ( 1 ) 913 2019.12

ISSN 2045-2322

The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2(+)SALL1(+) nephron progenitor cells with 92% efficiency within 2 days. Subsequently, the second set - HNF1A, GATA3, GATA1 and EMX2, differentiated these cells into PAX8(+)LHX1(+) pretubular aggregates in another 2 days. Further culture in both 2-dimensional and 3-dimensional conditions produced iNephLOs containing cells characterized as podocytes, proximal tubules, and distal tubules in an additional 10 days. Global gene expression profiles showed similarities between iNephLOs and the human adult kidney, suggesting possible uses of iNephLOs as in vitro models for kidneys.

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Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules

Futatsugi, Koji, Tokuyama, Hirobumi, Shibata, Shinsuke, Naitoh, Makiko, Kanda, Takeshi, Minakuchi, Hitoshi, Yamaguchi, Shintaro, Hayashi, Koichi, Minamishima, Yoji Andrew, Yanagita, Motoko, Wakino, Shu, Itoh, Hiroshi

SCIENTIFIC REPORTS 6 36533 2016.11

Research paper (scientific journal), Joint Work, ISSN 2045-2322

The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.

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miR-363 induces transdifferentiation of human kidney tubular cells to mesenchymal phenotype

Morizane, Ryuji, Fujii, Shizuka, Monkawa, Toshiaki, Hiratsuka, Ken, Yamaguchi, Shintaro, Homma, Koichiro, Itoh, Hiroshi

CLINICAL AND EXPERIMENTAL NEPHROLOGY 20 ( 3 ) 394 - 401 2016.06

Research paper (scientific journal), Joint Work, ISSN 1342-1751

BACKGROUND: microRNAs (miRNAs) are non-coding small RNAs that regulate embryonic development, cell differentiation and pathological processes via interaction with mRNA. Epithelial-mesenchymal transition (EMT) is pathological process that involves in a variety of diseases such as cancer or fibrosis. METHODS: In this study, we identified miR-363 as a potent inducer of EMT by microarray analysis in human kidney tubular cells, and analyzed the function and mechanisms of miR-363. RESULTS: Overexpression of miR-363 induced mesenchymal phenotypes with loss of epithelial phenotypes in human kidney tubular cells. In addition, in vitro scratch assay demonstrated that miR-363 promotes cell migration of primary culture of human kidney tubular cells. We identified TWIST/canonical WNT pathway as the downstream effecter of miR-363, and inhibition of canonical WNT by small molecule, IWR-1, attenuated EMT induced by miR-363. CONCLUSION: miR-363 induces transdifferentiation of human kidney tubular cells via upregulation of TWIST/canonical WNT pathway.

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The pathophysiological importance and therapeutic potential of NAD'biosynthesis and mitochondrial sirtuin SIRT3 in age-associated diseases

Yamaguchi, Shintaro and Yoshino, Jun

Nihon rinsho. Japanese Journal of Clinical Medicine 74 ( 9 ) 1447 - 1455 2016

ISSN 0047-1852

A case of severe osteomalacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomotic primary biliary cirrhosis

Yamaguchi, Shintaro, Maruyama, Tatsuya, Wakino, Shu, Tokuyama, Hirobumi, Hashiguchi, Akinori, Tada, Shinichiro, Homma, Koichiro, Monkawa, Toshiaki, Thomas, James, Miyashita, Kazutoshi, Kurihara, Isao, Yoshida, Tadashi, Konishi, Konosuke, Hayashi, Koichi, Hayashi, Matsuhiko, Itoh, Hiroshi

BMC NEPHROLOGY 16 394 - 401 2015.11

Research paper (scientific journal), Joint Work, ISSN 1471-2369

BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. CONCLUSION: In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not been recognized as a result of the renal involvement of PBC. PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver dysfunction.

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[The pathophysiological importance and therapeutic potential of NAD+ biosynthesis in age-related diseases]

Yamaguchi, S. and Yoshino, J.

Seikagaku 87 ( 2 ) 239 - 44 2015.04

ISSN 0037-1017

miR-34c attenuates epithelial-mesenchymal transition and kidney fibrosis with ureteral obstruction

Morizane, Ryuji, Fujii, Shizuka, Monkawa, Toshiaki, Hiratsuka, Ken, Yamaguchi, Shintaro, Homma, Koichiro, Itoh, Hiroshi

SCIENTIFIC REPORTS 4 394 - 401 2014.04

Research paper (scientific journal), Joint Work, ISSN 2045-2322

micro RNAs (miRNAs) are small non-coding RNAs that act as posttranscriptional repressors by binding to the 3'-UTR of target mRNAs. On the other hand, mesenchymal-epithelial transition (EMT) and kidney fibrosis is a pathological process of chronic kidney disease (CKD), and its relationship to miRNAs is becoming recognized as a potential target for CKD therapies. To find new miRNAs involved in EMT, we examined miRNA expression in experimental models of EMT and renal epithelialization using microarray, and found that miR-34c attenuates EMT induced by TGF-β in a mouse tubular cell line. To confirm the effects of miR-34c in vivo, we administered the precursor of miR-34c to mice with unilateral ureteral obstruction, and miR-34c decreased kidney fibrosis area and the expression of connective tissue growth factor, α-SMA, collagen type 1, collagen type 3 and fibronectin. In conclusion, our study showed miR-34c attenuates EMT and kidney fibrosis of mice with ureteral obstruction.

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Kidney Specific Protein-Positive Cells Derived from Embryonic Stem Cells Reproduce Tubular Structures In Vitro and Differentiate into Renal Tubular Cells

Morizane, Ryuji, Monkawa, Toshiaki, Fujii, Shizuka, Yamaguchi, Shintaro, Homma, Koichiro, Matsuzaki, Yumi, Okano, Hideyuki, Itoh, Hiroshi

PLOS ONE 8 ( 6 ) 394 - 401 2013.06

Research paper (scientific journal), Joint Work, ISSN 1932-6203

Embryonic stem cells and induced pluripotent stem cells have the ability to differentiate into various organs and tissues, and are regarded as new tools for the elucidation of disease mechanisms as well as sources for regenerative therapies. However, a method of inducing organ-specific cells from pluripotent stem cells is urgently needed. Although many scientists have been developing methods to induce various organ-specific cells from pluripotent stem cells, renal lineage cells have yet to be induced in vitro because of the complexity of kidney structures and the diversity of kidney-component cells. Here, we describe a method of inducing renal tubular cells from mouse embryonic stem cells via the cell purification of kidney specific protein (KSP)-positive cells using an anti-KSP antibody. The global gene expression profiles of KSP-positive cells derived from ES cells exhibited characteristics similar to those of cells in the developing kidney, and KSP-positive cells had the capacity to form tubular structures resembling renal tubular cells when grown in a 3D culture in Matrigel. Moreover, our results indicated that KSP-positive cells acquired the characteristics of each segment of renal tubular cells through tubular formation when stimulated with Wnt4. This method is an important step toward kidney disease research using pluripotent stem cells, and the development of kidney regeneration therapies.

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Renal microcirculation and calcium channel subtypes

Homma, Koichiro, Hayashi, Koichi, Yamaguchi, Shintaro, Fujishima, Seitaro, Hori, Shingo and Itoh, Hiroshi

Current hypertension reviews 9 ( 3 ) 182 - 186 2013

ISSN 1573-4021

Triglyceride-rich lipoproteins in chronic kidney disease patients undergoing maintenance haemodialysis treatment

Koichiro Homma, Yasuhiko Homma, Shintaro Yamaguchi, Yutaka Shiina, Shu Wakino, Koichi Hayashi, Shingo Hori, Hiroshi Itoh.

Int J Clin Pract 66 ( 4 ) 394 - 398 2012

Research paper (scientific journal), Joint Work

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Triglyceride‐rich lipoproteins in chronic kidney disease patients undergoing maintenance haemodialysis treatment

Homma, K, Homma, Y, Yamaguchi, S, Shiina, Y, Wakino, Shu, Hayashi, Koichi, Hori, Shingo and Itoh, H

International journal of clinical practice 66 ( 4 ) 394 - 398 2012

ISSN 1368-5031

Gastrointestinal pseudo-obstruction after debulking surgery of malignant pheochromocytoma, improved by intravenous administration of alpha-adrenergic receptor blocker, phentolamine

Yamaguchi, Shintaro, Shibata, Hirotaka, Miyashita, Kazutoshi, Kurihara, Isao, Murai-Takeda, Ayano, Mitsuishi, Yuko, Motosugi, Yuichiro, Saito, Yoshimasa, Hayashi, Koichi, Itoh, Hiroshi

HYPERTENSION RESEARCH 33 ( 7 ) 753 - 754 2010.07

Research paper (scientific journal), Joint Work, ISSN 0916-9636

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